What are the next steps for treating rectal cancer after FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, leucovorin) fails?

Treatment Options After FOLFIRINOX Failure in Rectal Cancer

For metastatic rectal cancer progressing after FOLFIRINOX, switch to an oxaliplatin-based regimen (FOLFOX or CAPOX) combined with bevacizumab, or consider regorafenib or trifluridine/tipiracil in later lines after standard therapies have been exhausted. 1

Second-Line Treatment Strategy

Primary Recommendation: Oxaliplatin-Based Regimens

• FOLFOX or CAPOX with bevacizumab is the preferred second-line option after FOLFIRINOX (which contains irinotecan) failure 1
• Bevacizumab continuation beyond progression improves overall survival (11.2 vs 9.8 months; HR 0.81, p=0.0062), making it appropriate to continue anti-angiogenic therapy even after first-line progression 1
• Aflibercept or ramucirumab combined with FOLFIRI can be used as alternatives to bevacizumab, though this represents continuing irinotecan exposure 1, 2

RAS/BRAF Status Considerations

• For RAS wild-type tumors with left-sided primary location: Consider cetuximab or panitumumab plus irinotecan (or as single agents if combination not tolerated) 1
• For RAS wild-type tumors with right-sided primary location: Prioritize bevacizumab-containing regimens over anti-EGFR therapy, as right-sided tumors respond poorly to EGFR inhibition 1
• For BRAF V600E-mutated tumors: Encorafenib plus cetuximab is the recommended option in second or third line (ESMO-MCBS score: 4) 1

Third-Line and Beyond

Standard Options After Multiple Prior Therapies

• Regorafenib (160 mg daily, days 1-21 of 28-day cycles) is FDA-approved for patients previously treated with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and (if RAS wild-type) anti-EGFR therapy 1, 3

  • Dose escalation strategy (80 mg week 1,120 mg week 2,160 mg week 3) improves tolerability in the first cycle 1
  • Monitor for hepatotoxicity, hand-foot skin reaction, and hypertension 3

• Trifluridine/tipiracil (35 mg/m² twice daily, days 1-5 and 8-12 every 28 days) is an alternative oral agent with similar indications 1

  • Combination with bevacizumab significantly prolongs overall survival and progression-free survival compared to monotherapy 1

Molecular-Directed Therapies

• HER2-amplified tumors (2-5% of colorectal cancers): Consider trastuzumab plus pertuzumab, trastuzumab plus lapatinib, or trastuzumab deruxtecan in third-line or later 1
• MSI-H/dMMR tumors: Ipilimumab-nivolumab is recommended after first-line chemotherapy failure (ESMO-MCBS score: 3) 1

Important Caveats and Pitfalls

Avoid Ineffective Agents

• Do not use capecitabine monotherapy, mitomycin, interferons, taxanes, methotrexate, pemetrexed, sunitinib, sorafenib, erlotinib, or gemcitabine as salvage therapy—these have not shown efficacy in this setting 1

Sequencing Considerations

• The order of receiving fluoropyrimidines, oxaliplatin, and irinotecan does not significantly impact overall survival, but exposure to all three agents during the continuum of care correlates with improved median survival 1
• Rechallenge with anti-EGFR antibodies may be considered in selected RAS wild-type patients who initially responded, though switching between cetuximab and panitumumab after resistance is not recommended 1

Locally Advanced Disease Context

• If the question pertains to locally advanced (non-metastatic) rectal cancer that progressed during neoadjuvant FOLFIRINOX, the approach differs: proceed to chemoradiotherapy followed by surgery as per the PRODIGE-23 protocol 4
• The PRODIGE-23 trial demonstrated that neoadjuvant FOLFIRINOX followed by chemoradiotherapy improved 3-year disease-free survival (76% vs 69%, HR 0.69, p=0.034) compared to standard chemoradiotherapy alone 4

Monitoring and Response Assessment

• Perform radiological evaluation every 8-12 weeks with CT or MRI and CEA levels during active treatment 1
• For patients achieving disease control, consider maintenance therapy with fluoropyrimidine alone or with bevacizumab to prolong progression-free survival 5